DESCRIPTION: Approximately 4.8 million Americans over the age of 65 currently suffer from age-related wound complications, with an annual expenditure of over $10 billion annually. The elderly are the most likely age group to undergo procedures resulting in surgical wounds, and due to skin changes that occur with advanced age, their skin is also more prone to acute dermal trauma. In addition, delayed cellular events and impaired angiogenic responses to injury increases the time required for these wounds to heal, and in turn, leaves patients more prone to complications such as infection, re-injury and chronic wound development. Valitor, Inc. is developing a protein-based therapy to accelerate neovascularization and improve the rate of wound healing in aged individuals. We designed our therapy to complement the standard practice of wound management and to reduce the costly serial effort required for treatment of these slowly healing wounds. Our patented technology is a chemical tethering process that provides enhanced potency, stability, and specificity of growth factors in vivo. With this technology, we have chemically conjugated Sonic hedgehog (Shh), an important angiogenic factor previously shown to stimulate neovascularization, to linear chains of hyaluronic acid (HyA), a soluble, biocompatible polymer. We can control the valency of growth factors that are delivered to a wound by varying the ratio of Shh:HyA, and we have demonstrated that the Shh valency of our conjugates can modulate their cellular bioactivity. Conjugating Shh to a large macromolecule may also prevent its deactivation by proteolytic enzymes and enhance its molecular stability in the target tissues. In Phase I, our overall goal is to develop mvShh conjugates that improve the mechanisms of wound healing in older individuals by enhancing the migration of endothelial cells (ECs) and accelerating wound neovascularization. In Specific Aim #1 we will develop mvShh conjugates to enhance endothelial cell activation and migration in vitro. In Specific Aim #2 we will evaluate the effect of mvShh on endothelial cell migration and neovascularization in vivo using a full- thickness excisional dermal wound model in 18-month-old mice. The wound size will also be measured periodically until full closure has been achieved. The tensile strength of the repaired tissue will then be evaluated. Our findings will provide valuable proof-of-concept data to guide further pre-clinical development of our drug therapy, which we have planned for Phase II of this project.